The role of metabolism in 2-methoxyethanol-induced testicular toxicity

Abstract

The role of metabolism in 2-methoxyethanol (ME)-induced testicular toxicity has been investigated with Sprague-Dawley rats. Following administration of [ 14C]ME (250 mg/kg, ip) to a group of animals, there was evidence of testicular damage, identified as depletion of the spermatocyte population. Radioactivity detected in urine over 48 hr after treatment accounted for 55% of the dose. The major urinary metabolites were identified by HPLC and isotope dilution analysis, as methoxyacetic acid (MAA) and methoxyacetylglycine (accounting for 50 to 60% and 18 to 25%, respectively, of urinary radioactivity). Analysis of plasma revealed a rapid conversion of ME to MAA ( t 1 2 for disappearance of ME = 0.6 ± 0.03 hr) and grdual clearance of radioactivity ( t 1 2 = 19.7 ± 2.3 hr ). Pretreatment of animals with pyrazole (400 mg/kg, ip) 1 hr prior to [ 14C]ME dosing gave complete protection against the testicular toxicity of ME. Radioactivity detected in the urine from the pyrazole-pretreated groups over 48 hr (18%) was significantly lower than in the ME-only group. The major radioactive peak co-chromatographed with ME (30 to 36% of the total urinary radioactivity). MAA and methoxyacetylglycine were not major metabolites. Analysis of plasma revealed almost complete inhibition of the conversion of ME to MAA ( t 1 2 for disappearance of ME = 42.6 ± 5.6 hr, clearance of radioactivity t 1 2 = 51.0 ± 7.8 hr ). The results demonstrate that metabolic activation is required for 2-methoxyethanol to exert toxicity to the male reproductive system.